tbuckley/cabot-search huggingface dataset:
Club Cell Secretory Protein in Lung Disease: Emerging Concepts and Potential Therapeutics
Authors: Tereza Martinu, Jamie L. Todd, Andrew E. Gelman, Stefano Guerra, Scott M. Palmer
Journal: Annual Review of Medicine (2022)

Club cell secretory protein (CCSP), also known as secretoglobin 1A1 (gene name SCGB1A1), is one of the most abundant proteins in the lung, primarily produced by club cells of the distal airway epithelium. At baseline, CCSP is found in large concentrations in lung fluid specimens and can also be detected in the blood and urine. Obstructive lung diseases are generally associated with reduced CCSP levels, thought to be due to decreased CCSP production or club cell depletion. Conversely, several restrictive lung diseases have been found to have increased CCSP levels both in the lung and in the circulation, likely related to club cell dysregulation as well as increasedlung permeability. Recent studies demonstrate multiple mechanisms by which CCSP dampens acute and chronic lung inflammation. Given these anti-inflammatory effects, CCSP represents a novel potential therapeutic modality in lung disease.
Clonal Hematopoiesis and Its Impact on Human Health
Authors: Herra Ahmad, Nikolaus Jahn, Siddhartha Jaiswal
Journal: Annual Review of Medicine (2022)

Aging is associated with increased mutational burden in every tissue studied. Occasionally, fitness-increasing mutations will arise, leading to stem cell clonal expansion. This process occurs in several tissues but has been best studied in blood. Clonal hematopoiesis is associated with an increased risk of blood cancers, such as acute myeloid leukemia, which result if additional cooperating mutations occur. Surprisingly, it is also associated with an increased risk of nonmalignant diseases, such as atherosclerotic cardiovascular disease. This may be due to enhanced inflammation in mutated innate immune cells, which could be targeted clinically with anti-inflammatory drugs. Recent studies have uncovered other factors that predict poor outcomes in patients with clonal hematopoiesis, such as size of the mutant clone, mutated driver genes, and epigenetic aging. Though clonality is inevitable and largely a function of time, recent work has shown that inherited genetic variation can also influence this process. Clonal hematopoiesis provides a paradigm for understanding how age-related changes in tissue stem cell composition and function influence human health.
Malaria outbreak in Laos driven by a selective sweep for Plasmodium falciparum kelch13 R539T mutants: a genetic epidemiology analysis
Authors: Varanya Wasakul, Areeya Disratthakit, Mayfong Mayxay, Keobouphaphone Chindavongsa, Viengphone Sengsavath, Nguyen Thuy-Nhien, Richard D Pearson, Sonexay Phalivong, Saiamphone Xayvanghang, Richard J Maude, Sónia Gonçalves, Nicholas P Day, Paul N Newton, Elizabeth A Ashley, Dominic P Kwiatkowski, Arjen M Dondorp, Olivo Miotto
Journal: The Lancet Infectious Diseases (2022)
Early‐life fecal metabolomics of food allergy
Authors: Kathleen A. Lee‐Sarwar, Yih‐Chieh Chen, Jessica Lasky‐Su, Rachel S. Kelly, Robert S. Zeiger, George T. O'Connor, Leonard B. Bacharier, Xiaojiong Jia, Avraham Beigelman, Diane R. Gold, Nancy Laranjo, Supinda Bunyavanich, Scott T. Weiss, Augusto A. Litonjua, Patrick J. Brennan
Journal: Allergy (2022)

Intestinal microenvironmental perturbations may increase food allergy risk. We hypothesize that children with clinical food allergy, those with food sensitization, and healthy children can be differentiated by intestinal metabolites in the first years of life.
Effect of colonisation with Neisseria lactamica on cross-reactive anti-meningococcal B-cell responses: a randomised, controlled, human infection trial
Authors: Adam P Dale, Anastasia A Theodosiou, Diane F Gbesemete, Jonathan M Guy, Eleanor F Jones, Alison R Hill, Muktar M Ibrahim, Hans de Graaf, Muhammad Ahmed, Saul N Faust, Andrew R Gorringe, Marta E Polak, Jay R Laver, Robert C Read
Journal: The Lancet Microbe (2022)
Discontinuation of RAS Inhibitors in Advanced CKD — Has Equipoise Occurred?
Authors: Julie R. Ingelfinger
Journal: New England Journal of Medicine (2022)

Blockade of the renin–angiotensin system (RAS) is renoprotective beyond the effect of lowering blood pressure, especially in patients with mild-to-moderate chronic kidney disease (CKD).1,2 However, such renoprotection is far more effective when patients with CKD have proteinuria.1,2 As nephrologists, we struggle about whether to continue prescribing RAS inhibitors to patients with advanced (stage 4 or 5) CKD, given the perceived risks. We hope that stopping such treatment may lead to an increase (however modest) in the estimated glomerular filtration rate (eGFR), and we worry about possible drug-related hyperkalemia and other adverse events if RAS inhibition is continued. Although recent retrospective . . .
Isoformic PD-1-mediated immunosuppression underlies resistance to PD-1 blockade in hepatocellular carcinoma patients
Authors: Zhiwu Tan, Mei Sum Chiu, Xinxiang Yang, Ming Yue, Tan To Cheung, Dongyan Zhou, Yuewen Wang, Anthony Wing-Hung Chan, Chi Wing Yan, Ka Yi Kwan, Yik Chun Wong, Xin Li, Jingying Zhou, Ka Fai To, Jiye Zhu, Chung Mau Lo, Alfred Sze-Lok Cheng, Stephen Lam Chan, Li Liu, You-Qiang Song, Kwan Man, Zhiwei Chen
Journal: Gut (2022)

Objective Immune checkpoint blockade (ICB) has improved cancer treatment, yet why most hepatocellular carcinoma (HCC) patients are resistant to PD-1 ICB remains elusive. Here, we elucidated the role of a programmed cell death protein 1 (PD-1) isoform, Δ42PD-1, in HCC progression and resistance to nivolumab ICB. Design We investigated 74 HCC patients in three cohorts, including 41 untreated, 28 treated with nivolumab and 5 treated with pembrolizumab. Peripheral blood mononuclear cells from blood samples and tumour infiltrating lymphocytes from tumour tissues were isolated for immunophenotyping. The functional significance of Δ42PD-1 was explored by single-cell RNA sequencing analysis and validated by functional and mechanistic studies. The immunotherapeutic efficacy of Δ42PD-1 monoclonal antibody was determined in HCC humanised mouse models. Results We found distinct T cell subsets, which did not express PD-1 but expressed its isoform Δ42PD-1, accounting for up to 71% of cytotoxic T lymphocytes in untreated HCC patients. Δ42PD-1 + T cells were tumour-infiltrating and correlated positively with HCC severity. Moreover, they were more exhausted than PD-1 + T cells by single T cell and functional analysis. HCC patients treated with anti-PD-1 ICB showed effective PD-1 blockade but increased frequencies of Δ42PD-1 + T cells over time especially in patients with progressive disease. Tumour-infiltrated Δ42PD-1 + T cells likely sustained HCC through toll-like receptors-4-signalling for tumourigenesis. Anti-Δ42PD-1 antibody, but not nivolumab, inhibited tumour growth in three murine HCC models. Conclusion Our findings not only revealed a mechanism underlying resistance to PD-1 ICB but also identified anti-Δ42PD-1 antibody for HCC immunotherapy.
Biallelic TLR4 deficiency in humans
Authors: Melania Capitani, Ahmad A. Al-Shaibi, Sumeet Pandey, Lisa Gartner, Henry Taylor, Satanay Z. Hubrack, Nourhen Agrebi, Muneera Jassim Al-Mohannadi, Saad Al Kaabi, Thomas Vogl, Johannes Roth, Daniel Kotlarz, Christoph Klein, Adrian K. Charles, Vinayan Vijayakumar, Mohammed Yousuf Karim, Bruce George, Simon P. Travis, Mamoun Elawad, Bernice Lo, Holm H. Uhlig
Journal: Journal of Allergy and Clinical Immunology (2022)

Toll-like receptors (TLRs) mediate functions for host defense and inflammatory responses. TLR4 recognizes LPS, a component of gram-negative bacteria as well as host-derived endogenous ligands such as S100A8 and S100A9 proteins.We sought to report phenotype and cellular function of individuals with complete TLR4 deficiency.We performed genome sequencing and investigated exome and genome sequencing databases. Cellular responses were studied on primary monocytes, macrophages, and neutrophils, as well as cell lines using flow cytometry, reporter, and cytokine assays.We identified 2 individuals in a family of Qatari origin carrying a homozygous stop codon variant p.Q188X in TLR4 presenting with a variable phenotype (asymptomatic and inflammatory bowel disease consistent with severe perianal Crohn disease). A third individual with homozygous p.Y794X was identified in a population database. In contrast to hypomorphic polymorphisms p.D299G and p.T399I, the variants p.Q188X and p.Y794X completely abrogated LPS-induced cytokine responses whereas TLR2 response was normal. TLR4 deficiency causes a neutrophil CD62L shedding defect, whereas antimicrobial activity toward intracellular Salmonella was intact.Biallelic TLR4 deficiency in humans causes an inborn error of immunity in responding to LPS. This complements the spectrum of known primary immunodeficiencies, in particular myeloid differentiation primary response 88 (MYD88) or the IL-1 receptor-associated kinase 4 (IRAK4) deficiency that are downstream of TLR4 and TLR2 signaling.
Cell type-specific changes identified by single-cell transcriptomics in Alzheimer’s disease
Authors: Tain Luquez, Pallavi Gaur, Ivy M Kosater, Matti Lam, Dylan I Lee, Jason Mares, Fahad Paryani, Archana Yadav, Vilas Menon
Journal: Genome Medicine (2022)

Abstract The rapid advancement of single-cell transcriptomics in neurology has allowed for profiling of post-mortem human brain tissue across multiple diseases. Over the past 3 years, several studies have examined tissue from donors with and without diagnoses of Alzheimer’s disease, highlighting key changes in cell type composition and molecular signatures associated with pathology and, in some cases, cognitive decline. Although all of these studies have generated single-cell/nucleus RNA-seq or ATAC-seq data from the full array of major cell classes in the brain, they have each focused on changes in specific cell types. Here, we synthesize the main findings from these studies and contextualize them in the overall space of large-scale omics studies of Alzheimer’s disease. Finally, we touch upon new horizons in the field, in particular advancements in high-resolution spatial interrogation of tissue and multi-modal efforts—and how they are likely to further advance mechanistic and target-selection studies on Alzheimer’s disease.
Z-DNA enhances immunotherapy by triggering death of inflammatory cancer-associated fibroblasts
Authors: Alan Herbert, Siddharth Balachandran
Journal: Journal for ImmunoTherapy of Cancer (2022)

Cancer-associated fibroblasts (CAFs) are a heterogeneous population of cells. At one end of the spectrum are alpha-smooth muscle actin expressing myoCAFs (myofibroblast CAFs) and at the other end are the interferon (IFN) and Janus Kinase/Signal Transducer and Activator of Transcription responsive iCAFs (inflammatory CAFs). Both types of CAFs promote tumor growth. While myoCAFs foster immune exclusion and limit tumor spread, iCAFs create a highly immunosuppressive environment and foster the seeding of distant metastases. However, iCAFs also represent a tumor vulnerability. They are competent to undergo necroptosis, a highly immunogenic form of cell death that is triggered when Z-DNA or Z-RNA (collectively called ZNA) is sensed by the IFN-induced ZNA binding protein 1 (ZBP1). The sequestering of ZNA ligands by the p150 isoform of the double-stranded RNA-specific deaminase ADAR1 protects iCAFs from cell death. ZBP1-dependent necroptosis in iCAFs can be triggered by administering an orally available small molecule that generates sufficient amounts of ZNA to bypass ADAR1 inhibition. The therapeutic approach of targeting Z-prone sequences (called flipons) is agnostic to the mutations driving cancer progression. By exploiting the tumor vulnerability posed by expression of ZBP1-dependent immunogenic cell death pathways in iCAFs, flipon therapeutics offer new hope for improved clinical outcomes.
Risk of melanoma and nonmelanoma skin cancer with immunosuppressants, part I: Calcineurin inhibitors, thiopurines, IMDH inhibitors, mTOR inhibitors, and corticosteroids
Authors: Margaret Ann Kreher, Mary Margaret B. Noland, Sailesh Konda, Maria I. Longo, Rodrigo Valdes-Rodriguez
Journal: Journal of the American Academy of Dermatology (2022)
Authors’ Reply to Denning: Comment on: “Global Consumption Trend of Antifungal Agents in Humans From 2008 to 2018: Data From 65 Middle- and High-Income Countries”
Authors: Swathi Pathadka, Vincent K. C. Yan, Chin Fen Neoh, Daoud Al-Badriyeh, David C. M. Kong, Monica A. Slavin, Benjamin J. Cowling, Ivan F. N. Hung, Ian C. K. Wong, Esther W. Chan
Journal: Drugs (2022)
Early T-bet promotes LFA1 upregulation required for CD8+ effector and memory T cell development
Authors: Gretchen Harms Pritchard, Anthony T. Phan, David A. Christian, Trevor J. Blain, Qun Fang, John Johnson, Nathan H. Roy, Lindsey Shallberg, Ross M. Kedl, Christopher A. Hunter
Journal: The Journal of Experimental Medicine (2022)

The T-box transcription factor T-bet is regarded as a "master regulator" of CD4+ Th1 differentiation and IFN-γ production. However, in multiple models of infection, T-bet appears less critical for CD8+ T cell expansion and effector function. Here, we show that following vaccination with a replication-deficient strain of Toxoplasma gondii, CD8+ T cell expression of T-bet is required for optimal expansion of parasite-specific effector CD8+ T cells. Analysis of the early events associated with T cell activation reveals that the α chain of LFA1, CD11a, is a target of T-bet, and T-bet is necessary for CD8+ T cell upregulation of this integrin, which influences the initial priming of CD8+ effector T cells. We propose that the early expression of T-bet represents a T cell-intrinsic factor that optimizes T-DC interactions necessary to generate effector responses.
Poor housing and dark satanic mills
Authors: Kamran Abbasi
Journal: BMJ (2022)

Articles inThe BMJ this week featuring mills and housing may seem like a throwback, but the problems they raise, from science to social welfare, are very contemporary.The impact of the cost of living crisis is clear for health professionals to see, and, where once poor laws offered relief to people who were disadvantaged, recent law making and spending plans will not do enough for people feeling the "consequences of creaking public services in a nation getting poorer" (
Global chromatin landscapes identify candidate noncoding modifiers of cardiac rhythm
Authors: Samadrita Bhattacharyya, Rahul K. Kollipara, Gabriela Orquera-Tornakian, Sean Goetsch, Minzhe Zhang, Cameron Perry, Boxun Li, John M. Shelton, Minoti Bhakta, Jialei Duan, Yang Xie, Guanghua Xiao, Bret M. Evers, Gary C. Hon, Ralf Kittler, Nikhil V. Munshi
Journal: Journal of Clinical Investigation (2022)

Comprehensive cis-regulatory landscapes are essential for accurate enhancer prediction and disease variant mapping. Although cis-regulatory element (CRE) resources exist for most tissues and organs, many rare - yet functionally important - cell types remain overlooked. Despite representing only a small fraction of the heart's cellular biomass, the cardiac conduction system (CCS) unfailingly coordinates every life-sustaining heartbeat. To globally profile the mouse CCS cis-regulatory landscape, we genetically tagged CCS component-specific nuclei for comprehensive assay for transposase-accessible chromatin-sequencing (ATAC-Seq) analysis. Thus, we established a global CCS-enriched CRE database, referred to as CCS-ATAC, as a key resource for studying CCS-wide and component-specific regulatory functions. Using transcription factor (TF) motifs to construct CCS component-specific gene regulatory networks (GRNs), we identified and independently confirmed several specific TF sub-networks. Highlighting the functional importance of CCS-ATAC, we also validated numerous CCS-enriched enhancer elements and suggested gene targets based on CCS single-cell RNA-Seq data. Furthermore, we leveraged CCS-ATAC to improve annotation of existing human variants related to cardiac rhythm and nominated a potential enhancer-target pair that was dysregulated by a specific SNP. Collectively, our results established a CCS-regulatory compendium, identified novel CCS enhancer elements, and illuminated potential functional associations between human genomic variants and CCS component-specific CREs.
Nociception and pain in humans lacking a functional TRPV1 channel
Authors: Ben Katz, Rachel Zaguri, Simon Edvardson, Channa Maayan, Orly Elpeleg, Shaya Lev, Elyad Davidson, Maximilian Peters, Shlomit Kfir-Erenfeld, Esther Berger, Shifa Ghazalin, Alexander M. Binshtok, Baruch Minke
Journal: Journal of Clinical Investigation (2022)

BACKGROUNDChronic pain is a debilitating illness with currently limited therapy, in part due to difficulties in translating treatments derived from animal models to patients. The transient receptor potential vanilloid 1 (TRPV1) channel is associated with noxious heat detection and inflammatory pain, and reports of adverse effects in human trials have hindered extensive efforts in the clinical development of TRPV1 antagonists as novel pain relievers.METHODSWe examined 2 affected individuals (A1 and A2) carrying a homozygous missense mutation in TRPV1, rendering the channel nonfunctional. Biochemical and functional assays were used to analyze the mutant channel. To identify possible phenotypes of the affected individuals, we performed psychophysical and medical examinations.RESULTSWe demonstrated that diverse TRPV1 activators, acting at different sites of the channel protein, were unable to open the cloned mutant channel. This finding was not a consequence of impairment in the expression, cellular trafficking, or assembly of protein subunits. The affected individuals were insensitive to application of capsaicin to the mouth and skin and did not demonstrate aversive behavior toward capsaicin. Furthermore, quantitative sensory testing of A1 revealed an elevated heat-pain threshold but also, surprisingly, an elevated cold-pain threshold and extensive neurogenic inflammatory, flare, and pain responses following application of the TRPA1 channel activator mustard oil.CONCLUSIONOur study provides direct evidence in humans for pain-related functional changes linked to TRPV1, which is a prime target in the development of pain relievers.FUNDINGSupported by the Israel Science Foundation (368/19); Teva's National Network of Excellence in Neuroscience grant (no. 0394886) and Teva's National Network of Excellence in Neuroscience postdoctoral fellowship.
The genomic and immune landscape of long-term survivors of high-grade serous ovarian cancer
Authors: Dale W. Garsed, Ahwan Pandey, Sian Fereday, Catherine J. Kennedy, Kazuaki Takahashi, Kathryn Alsop, Phineas T. Hamilton, Joy Hendley, Yoke-Eng Chiew, Nadia Traficante, Pamela Provan, Dinuka Ariyaratne, George Au-Yeung, Nicholas W. Bateman, Leanne Bowes, Alison Brand, Elizabeth L. Christie, Julie M. Cunningham, Michael Friedlander, Bronwyn Grout, Paul Harnett, Jillian Hung, Bryan McCauley, Orla McNally, Anna M. Piskorz, Flurina A. M. Saner, Robert A. Vierkant, Chen Wang, Stacey J. Winham, Paul D. P. Pharoah, James D. Brenton, Thomas P. Conrads, George L. Maxwell, Susan J. Ramus, Celeste Leigh Pearce, Malcolm C. Pike, Brad H. Nelson, Ellen L. Goode, Anna DeFazio, David D. L. Bowtell
Journal: Nature Genetics (2022)
Chronic viral coinfections differentially affect the likelihood of developing long COVID
Authors: Michael J. Peluso, Tyler-Marie Deveau, Sadie E. Munter, Dylan Ryder, Amanda Buck, Gabriele Beck-Engeser, Fay Chan, Scott Lu, Sarah A. Goldberg, Rebecca Hoh, Viva Tai, Leonel Torres, Nikita S. Iyer, Monika Deswal, Lynn H. Ngo, Melissa Buitrago, Antonio Rodriguez, Jessica Y. Chen, Brandon C. Yee, Ahmed Chenna, John W. Winslow, Christos J. Petropoulos, Amelia N. Deitchman, Joanna Hellmuth, Matthew A. Spinelli, Matthew S. Durstenfeld, Priscilla Y. Hsue, J. Daniel Kelly, Jeffrey N. Martin, Steven G. Deeks, Peter W. Hunt, Timothy J. Henrich
Journal: Journal of Clinical Investigation (2022)

BACKGROUND. The presence and reactivation of chronic viral infections, such as EBV, CMV, and HIV, have been proposed as potential contributors to long COVID (LC), but studies in well-characterized postacute cohorts of individuals with COVID-19 over a longer time course consistent with current case definitions of LC are limited.
Angiopoietin-like 3-derivative LNA043 for cartilage regeneration in osteoarthritis: a randomized phase 1 trial
Authors: Nicole Gerwin, Celeste Scotti, Christine Halleux, Mara Fornaro, Jimmy Elliott, Yunyu Zhang, Kristen Johnson, Jian Shi, Sandra Walter, Yufei Li, Carsten Jacobi, Nelly Laplanche, Magali Belaud, Jochen Paul, Gustavo Glowacki, Thomas Peters, Keith A. Wharton, Igor Vostiar, Florine Polus, Ina Kramer, Sabine Guth, Abdelkader Seroutou, Subhajit Choudhury, Didier Laurent, Joseph Gimbel, Jörg Goldhahn, Matthias Schieker, Sophie Brachat, Ronenn Roubenoff, Michaela Kneissel
Journal: Nature Medicine (2022)

Osteoarthritis (OA) is a common, debilitating, chronic disease with no disease-modifying drug approved to date. We discovered LNA043-a derivative of angiopoietin-like 3 (ANGPTL3)-as a potent chondrogenesis inducer using a phenotypic screen with human mesenchymal stem cells. We show that LNA043 promotes chondrogenesis and cartilage matrix synthesis in vitro and regenerates hyaline articular cartilage in preclinical OA and cartilage injury models in vivo. LNA043 exerts at least part of these effects through binding to the fibronectin receptor, integrin α5β1 on mesenchymal stem cells and chondrocytes. In a first-in-human (phase 1), randomized, double-blinded, placebo-controlled, single ascending dose, single-center trial ( NCT02491281 ; sponsored by Novartis Pharmaceuticals), 28 patients with knee OA were injected intra-articularly with LNA043 or placebo (3:1 ratio) either 2 h, 7 d or 21 d before total knee replacement. LNA043 met its primary safety endpoint and showed short serum pharmacokinetics, cartilage penetration and a lack of immunogenicity (secondary endpoints). Post-hoc transcriptomics profiling of cartilage revealed that a single LNA043 injection reverses the OA transcriptome signature over at least 21 d, inducing the expression of hyaline cartilage matrix components and anabolic signaling pathways, while suppressing mediators of OA progression. LNA043 is a novel disease-modifying OA drug candidate that is currently in a phase 2b trial ( NCT04864392 ) in patients with knee OA.
Inspiratory hyperoxia: a new way to prevent metastasis through metabolism reprogramming in non-small cell lung cancer
Authors: Beatrice Eymin
Journal: European Respiratory Journal (2022)

Lung cancer is one of the most frequently diagnosed cancers and the leading cause of cancer-related deaths worldwide [1]. Non-small cell lung cancer (NSCLC) accounts for the majority of all lung cancer cases. In the past decades, significative improvements in the clinical management of NSCLC patients have been made, first with the introduction of targeted therapies, such as inhibitors of the tyrosine kinase activity of epidermal growth factor receptor (EGFR) in EGFR-mutated NSCLC patients, and even more with the introduction of immune checkpoint inhibitors in NSCLC patients with high PD-L1 expression [2, 3]. However, despite impressive results, first responder patients always develop resistance, which correlates with disease progression. In addition, a significant proportion of NSCLC patients remains ineligible for these therapies or, even when eligible, does not respond. Therefore, the identification of new therapeutic strategies is of critical importance in NSCLC. When hyperoxia meets metabolism in non-small cell lung cancer <https://bit.ly/3Bj2Vvr>